Middle East Respiratory Syndrome coronavirus (MERS-CoV), a newly emergent subgroup C betacoronavirus, was first isolated from the Arabian Peninsula in 2012. Similar to the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) that emerged in China in 2002, MERS-CoV causes severe and often lower respiratory tract infection, occasionally accompanied by renal disease. As of Feb. 28, 2014, 184 cases with 80 deaths have been confirmed in 10 countries in the Middle East, Europe, and North Africa. Although the human-to-human transmission rate is mild to moderate at the moment, the increasing number of person-to-person transmissions raises the concern of a more widespread regional outbreak or even global spread by international travelers, similar to what occurred with SARS-CoV in 2002-2003. Limited information exists on the mechanisms that confer increased human-to-human transmission of MERS-CoV. However, mutational adaptation of the SARS-CoV Spike (S) protein for its receptor, angiotensin-converting enzyme 2 (ACE2) was a positive selection factor after zoonotic transfer to humans.
Phylogenetic analysis indicates that MERS-CoV is closely related to CoVs detected in Tylonycteris pachypus and Pipistrellus abramus bats in China, Nyctinomops laticaudatus bats in Mexico, and Nycteris cf. gambiensis bats in Ghana and Europe. A ˜190 base pair nucleotide fragment that was genetically identical to the RNA-dependent RNA polymerase of MERS-CoV was detected in Taphozous perforatus bat specimens in the vicinity of the index case in Saudi Arabia. Two independent serological surveys of livestock found that dromedary camels had a high prevalence of neutralizing antibodies (nAbs) against MERS-CoV. Recently, MERS-CoV has been identified from dromedary camels on a farm associated with 2 human cases, but the transmission patterns remain unclear. More recently, a study detected antibodies (Abs) in all 151 dromedary camel serum samples obtained from the United Arab Emirates in 2003, implying that MERS-CoV or closely related CoVs existed in the United Arab Emirates long before the first human MERS cases. A screen of cell lines derived from livestock and peridomestic small mammals on the Arabian Peninsula revealed that only ungulates such as goats and camels showed efficient replication of MERS-CoV. These findings suggest that bats and camels may play an important role in MERS-CoV transmission and that the range of species that can be infected with MERS-CoV may be even broader than currently known.
The coronavirus S protein is a class I membrane fusion protein that represent the major envelope protein on the surface of CoVs. The S protein presents as a trimer and mediates receptor binding, membrane fusion, and virus entry. S is also the major target for nAbs. It has been reported that MERS-CoV infected patients generated S-protein-specific nAbs. The cellular receptor for MERS-CoV has been identified to be dipeptidyl peptidase 4 (DPP4, CD26), which is conserved across many species. The receptor-binding domain (RBD) of the virus S protein in complex with human DPP4 (hDPP4) has been characterized.
Although MERS-CoV has a lower reproduction number (R0) than SARS-CoV (0.69 vs. 0.80), it has a much higher mortality rate than SARS-CoV (43% vs. 10%). Currently, there are no licensed vaccines or antivirals available for the prevention or treatment of MERS. Combination treatment with interferon-alpha2β and ribavirin can moderate the host response and has been reported to improve clinical outcomes in MERS-CoV-infected rhesus macaques. MERS-CoV S protein vaccines based on modified vaccinia virus Ankara or Venezuelan Equine Encephalitis Replicon Particles and purified RBD can induce virus nAbs in mouse models. However, results of human studies have not been reported. Thus, there remains an urgent medical need for the targeted prophylaxis and treatment of MERS.
Accordingly, there is an urgent need for therapeutics and prophylactic methods for preventing Middle East Respiratory Syndrome coronavirus infection, and diseases and disorders related thereto